Nuclear DJ-1 Regulates DNA Damage Repair via the Regulation of PARP1 Activity.

DNA damage and defective DNA repair are extensively linked to neurodegeneration in Parkinson's disease (PD), but the underlying molecular mechanisms remain poorly understood. Here, we determined that the PD-associated protein DJ-1 plays an essential role in modulating DNA double-strand break (DSB) repair. Specifically, DJ-1 is a DNA damage response (DDR) protein that can be recruited to DNA damage sites, where it promotes DSB repair through both homologous recombination and nonhomologous end joining. Mechanistically, DJ-1 interacts directly with PARP1, a nuclear enzyme essential for genomic stability, and stimulates its enzymatic activity during DNA repair. Importantly, cells from PD patients with the DJ-1 mutation also have defective PARP1 activity and impaired repair of DSBs. In summary, our findings uncover a novel function of nuclear DJ-1 in DNA repair and genome stability maintenance, and suggest that defective DNA repair may contribute to the pathogenesis of PD linked to DJ-1 mutations.

Parkin regulates microglial NLRP3 and represses neurodegeneration in Parkinson's disease.

Microglial hyperactivation of the NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) inflammasome contributes to the pathogenesis of Parkinson's disease (PD). Recently, neuronally expressed NLRP3 was demonstrated to be a Parkin polyubiquitination substrate and a driver of neurodegeneration in PD. However, the role of Parkin in NLRP3 inflammasome activation in microglia remains unclear. Thus, we aimed to investigate whether Parkin regulates NLRP3 in microglia. We investigated the role of Parkin in NLRP3 inflammasome activation through the overexpression of Parkin in BV2 microglial cells and knockout of Parkin in primary microglia after lipopolysaccharide (LPS) treatment. Immunoprecipitation experiments were conducted to quantify the ubiquitination levels of NLRP3 under various conditions and to assess the interaction between Parkin and NLRP3. In vivo experiments were conducted by administering intraperitoneal injections of LPS in wild-type and Parkin knockout mice. The Rotarod test, pole test, and open field test were performed to evaluate motor functions. Immunofluorescence was performed for pathological detection of key proteins. Overexpression of Parkin mediated NLRP3 degradation via K48-linked polyubiquitination in microglia. The loss of Parkin activity in LPS-induced mice resulted in excessive microglial NLRP3 inflammasome assembly, facilitating motor impairment, and dopaminergic neuron loss in the substantia nigra. Accelerating Parkin-induced NLRP3 degradation by administration of a heat shock protein (HSP90) inhibitor reduced the inflammatory response. Parkin regulates microglial NLRP3 inflammasome activation through polyubiquitination and alleviates neurodegeneration in PD. These results suggest that targeting Parkin-mediated microglial NLRP3 inflammasome activity could be a potential therapeutic strategy for PD.

Association of Concurrent Olfactory Dysfunction and Probable Rapid Eye Movement Sleep Behavior Disorder with Early Parkinson's Disease Progression.

Background: Parkinson's disease (PD), with either rapid eye movement sleep behavior disorder (RBD) or olfactory dysfunction (OD), has been associated with disease progression. However, there is currently heterogeneity in predicting prognosis. Objectives: To identify whether the concurrent presence of OD and probable RBD (pRBD) in PD (Dual hit in PD, PD-DH) is associated with disease progression. Methods: We included 420 patients with de novo PD from the Parkinson's Progression Markers Initiative: 180 PD only (PD), 82 PD with OD (PD-OD), 94 PD with pRBD (PD-pRBD), and 64 PD with both OD and pRBD (PD-DH). Participants underwent motor and nonmotor evaluations, dopamine transporter imaging, and cerebrospinal fluid (CSF) assessment. Data were analyzed with generalized estimating equations and Cox proportional hazards analysis. Results: The PD-DH subtype was associated with higher scores and faster progression rates in Movement Disorder Society-Unified PD Rating Scale (MDS-UPDRS) Parts II and III. Also, patients in PD-DH group had faster deterioration in nonmotor symptoms, including MDS-UPDRS Part I score, Montreal Cognitive Assessment, Hopkins Verbal Learning Test-Revised, Wechsler Memory Scale-Third edition (WMS-III) Letter Number Sequencing score, Symbol Digit Modalities Test, and Scales for Outcomes in PD-Autonomic scores, with all P values <0.002. Moreover, the PD-DH subtype had a higher mild cognitive impairment risk (hazard ratio = 1.756, 95% confidence interval [CI] = 1.132-2.722; P = 0.012), faster decline in caudate standard uptake values (ß = -0.03, 95% CI = -0.06 to -0.008, P = 0.012), and CSF α-synuclein levels (ß = -77, 95% CI = -149 to -5, P = 0.034) than the PD group. Conclusion: Coexisting pRBD and OD in patients with PD may be associated with faster progressions in motor measurements and in cognitive and autonomic symptoms, indicating PD-DH as a more aggressive subtype for PD.

Mitochondrial morphology and synaptic structure altered in the retina of parkin-deficient mice.

Mutations in the PRKN gene are the major cause of autosomal recessive Parkinson's disease (PD). However, studies of parkin-/- mice did not show the loss of dopaminergic neurons and motor phenotypes at a young age. Whether pathological changes are associated with nonmotor symptoms of PD remains unclear. Visual impairment is one common nonmotor symptom in patients with PD. This study aimed to examine the effects of parkin-/- on mitochondria and synaptic structures in the retina of 6-month-old mice. Compared with wild-type mice, parkin-/- mice exhibited a slightly thickened retina. Also, the number of normal mitochondria (mito-5 grade) in rod spherules (RSs) significantly decreased (p < 0.01), the average area of mitochondria was significantly larger (p < 0.001), and the number of ribbons in RSs significantly decreased (p = 0.02). The RSs of parkin-/- mice showed severe swelling after flicker stimulation. Our study implicated that parkin-/- led to the impairment of mitochondria and abnormality of the synaptic structure in mouse retina at a young age, which damaged the synaptic transmission between photoreceptors and second-order retinal neurons and resulted in visual impairment.

Quercetin Protects against MPP+/MPTP-Induced Dopaminergic Neuron Death in Parkinson's Disease by Inhibiting Ferroptosis.

Ferroptosis, a novel form of regulated cell death, is caused by accumulation of lipid peroxides and excessive iron deposition. This process has been linked to the death of dopaminergic neurons in substantia nigra compacta (SNc) of Parkinson's disease (PD) patients. Quercetin (QCT), a natural flavonoid, has multiple pharmacological activities. However, it has not been established whether QCT can protect against dopaminergic neuron death by inhibiting ferroptosis. In this study, we investigated the potential antiferroptotic effects of QCT in cellular models established using specific ferroptosis inducers (Erastin and RSL-3) and MPP+. The effects were also explored using MPTP-induced PD mouse models. The cell counting kit-8 (CCK-8) assay was performed to assess cell viability. Variations in mitochondrial morphology were evaluated by transmission electron microscopy (TEM) while the mitochondrial membrane potential, mass, and ROS were measured by fluorescent probes. Lipid peroxidation levels were assayed through measurement of lipid ROS, MDA, GSH, and SOD levels. The effects of QCT on MPTP-induced behavioral disorders were examined by rotarod and open field tests. In vitro and in vivo, QCT significantly inhibited ferroptosis by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) protein. Additionally, QCT ameliorated motor behavioral impairments and protected against the loss of dopaminergic neurons in MPTP-induced PD models. Interestingly, Nrf2 knockdown alleviated the protective effects of QCT against ferroptosis. In conclusion, these results demonstrate that ferroptosis is involved in MPP+/MPTP-induced PD, and QCT inhibits ferroptosis by activating the Nrf2 protein. Therefore, QCT is a potential agent for preventing the loss of dopaminergic neurons by targeting ferroptosis.

Apolipoprotein E Genotype Contributes to Motor Progression in Parkinson's Disease.

BACKGROUND: Emerging evidence indicates that the apolipoprotein E (APOE) ε4 exacerbates α-synuclein pathology. OBJECTIVE: To determine whether APOE ε4 contributes to motor progression in early Parkinson's disease (PD). METHODS: Longitudinal data were obtained from 384 patients with PD divided into APOE ε4 carriers (n = 85) and noncarriers (n = 299) in the Parkinson's Progression Marker Initiative. Participants underwent yearly motor assessments over a mean follow-up period of 78.9 months. Repeated measures and linear mixed models were used to test the effects of APOE ε4. RESULTS: The motor progression was significantly more rapid in patients with PD carrying APOE ε4 than in noncarriers (ß = 0.283, P = 0.026, 95% confidence interval: 0.033-0.532). Through subgroup analysis, we found that the effect of APOE ε4 was significant only in patients with high amyloid ß burden (ß = 0.761, P < 0.001, 95% confidence interval: 0.0356-1.167). CONCLUSIONS: APOE ε4 may be associated with rapid motor progression in PD. © 2021 International Parkinson and Movement Disorder Society.

Study of the collagen type VI alpha 3 (COL6A3) gene in Parkinson's disease.

BACKGROUND: To date, the genetic contribution to Parkinson's disease (PD) remains unclear. Mutations in the collagen type VI alpha 3 (COL6A3) gene were recently identified as a cause of isolated dystonia. Since PD and dystonia are closely related disorders with shared clinical and genetic characteristics, we explored the association between COL6A3 and PD in a Chinese cohort. METHODS: We performed genetic screening of COL6A3 in a Chinese cohort of 173 patients with sporadic PD and 200 healthy controls. We identified variants that are likely to have pathogenic effects based on: 1) a minor allele frequency of < 0.01; and 2) the variant being recognized as deleterious by at least 15 different in silico predicting tools. Finally, we tested the aggregate burden of COL6A3 on PD via SKAT-O analysis. RESULTS: First, we found compound heterozygous COL6A3 gene mutations in one early-onset PD patients. Then, we explored whether COL6A3 variants contributed to increased risk of developing PD in a Chinese population. We detected 21 rare non-synonymous variants. Pathogenicity predictions identified 7 novel non-synonymous variants as likely to be pathogenic. SKAT-O analysis further revealed that an aggregate burden of variants in COL6A3 contributes to PD (p = 0.038). CONCLUSION: An increased aggregate burden of the COL6A3 gene was detected in patients with PD.

Genetic analysis of arylsulfatase A (ARSA) in Chinese patients with Parkinson's disease.

Recently, the arylsulfatase A (ARSA) variant c.899 T > C (p.L300S) was identified to be segregated with Parkinson's disease (PD) in one family of Japanese descent. And the variant c.1055A > G (p.N352S) of ARSA was reported as a risk reduction factor for PD in a Japanese population. To further investigate the relationship between ARSA and PD, we screened these two loci of the ARSA gene in 407 sporadic PD patients and 471 healthy controls from a Chinese Han population. However, we did not detect the ARSA p.L300S variant in either PD patients or healthy controls. Moreover, in case-control association analysis, the p.N325S variant showed no significant association with PD. Therefore, these results suggested that these ARSA variants may not be common genetic factors for sporadic PD in Chinese Han population.